Xiang Xuelian, Xu Mengtao, Liu Li, Meng Nuo, Lei Yu, Feng Yong, Tang Guodu
Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, China.
Sci Rep. 2024 Apr 25;14(1):9548. doi: 10.1038/s41598-024-60159-7.
Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.
铁死亡与包括急性胰腺炎（AP）在内的炎症性疾病密切相关；然而，铁死亡在高甘油三酯血症性胰腺炎（HTGP）中的作用仍不清楚。在本研究中，我们旨在探讨HTGP中脂质代谢与铁死亡之间的关系以及脂氧素A1（Lip-1）在体内的缓解作用。本研究首次探索了HTGP中的脂质代谢和内质网应激（ERS），将铁死亡作为HTGP的关键因素。在高脂饮食条件下诱导高甘油三酯血症（HTG）。然后注射雨蛙肽以建立AP和HTGP模型。分别在大鼠诱导AP和HTGP之前给予特异性铁死亡抑制剂Lip-1。检测血清甘油三酯、淀粉酶、炎症因子、病理和超微结构、脂质过氧化以及与铁死亡相关的铁过载指标。此外，评估了铁死亡与ERS之间的相互作用。我们发现HTG可加剧AP的发展，炎症反应增加且铁死亡过程加剧。Lip-1治疗可通过脂质代谢抑制铁死亡并进一步抵抗ERS相关蛋白的激活来减轻胰腺损伤。总的来说，我们的结果证明脂质代谢可通过调节ACSL4/LPCAT3蛋白水平促进HTGP中的铁死亡。此外，ERS可能通过Bip/p-EIF2α/CHOP途径参与铁死亡，随后Lip-1在大鼠模型中发挥缓解作用。
